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SUMMARY

The human T-lymphotropic viruses, type I (HTLV-I) and type II
(HTLV-II), are closely related but distinct retroviruses that can
infect humans. They are different from the human immunodeficiency
viruses that cause acquired immunodeficiency syndrome. Screening of
the U.S. blood supply for HTLV-I/II, which began in 1988,
identifies HTLV-I- and HTLV-II-infected persons who should be
counseled regarding their infections. This document summarizes
current information about HTLV, types I and II, and presents
recommendations developed by CDC and a U.S. Public Health Service
working group for counseling HTLV-I- and HTLV-II-infected persons.

INTRODUCTION

Human T-lymphotropic viruses, type I (HTLV-I) and type II
(HTLV-II), were the first human retroviruses discovered (1,2). Both
belong to the oncovirus subfamily of retroviruses and can transform
human lymphocytes so that they are self-sustaining in vitro. They
are only distantly related to the human immunodeficiency viruses
(HIV-1 and HIV-2), which belong to the lentivirus subfamily of
retroviruses and which cause acquired immunodeficiency syndrome
(AIDS). Infections with HTLV-I and HTLV-II are most easily detected
serologically. The presence of antibodies to HTLV-I or HTLV-II
indicates that a person is infected with the virus.

In November 1988, the Food and Drug Administration (FDA)
recommended that blood donation centers screen the U.S. blood
supply for HTLV-I (3). Since then, all donations of whole blood and
blood components in the United States have been screened for
antibodies to HTLV-I. The screening tests that were licensed, as
well as the investigational supplementary tests used to confirm
seroreactivity (Western immunoblot and radioimmunoprecipitation
assay), do not reliably differentiate between antibodies to HTLV-I
and the closely related HTLV-II. In addition, the licensed
screening tests, which use HTLV-I antigens, vary in their
sensitivity to detect antibodies to HTLV-II (4,5).
Approximately 2,000 HTLV-I/II-infected volunteer blood donors
were identified in the first year of screening in the United
States; testing, after amplification by polymerase chain reaction,
indicated that approximately half were infected with HTLV-I and
half with HTLV-II (6). Such donors are counseled and permanently
deferred from donating blood. Because the polymerase chain-reaction
test is not routinely available, many donors and other persons
positive by serologic assays have been told that they are infected
with HTLV-I/II. The uncertainty regarding the identity of the
infecting virus and the differing epidemiologic and clinical
correlates of HTLV-I and HTLV-II infections have complicated
counseling of HTLV-I/II-infected persons.

Until recently, the only reliable way to differentiate HTLV-I
from HTLV-II infection was by polymerase chain reaction (7). Within
the past 2 years, investigational peptide- and recombinant
protein-based serologic assays that can more easily differentiate
the antibodies to HTLV-I and HTLV-II have been developed (8,9).
Preliminary data suggest that these investigational tests are
potentially useful for typing serum samples (8,9).

The recommendations for counseling HTLV-I-, HTLV-II-, and
HTLV-I/II-infected persons included in this document are intended
for use by health-care workers and public health officials in the
United States. They may not be applicable in developing countries,
where the need for breast-feeding may outweigh concerns about
transmission of these viruses.

HTLV-I

Prevalence

HTLV-I infection is endemic in southwestern Japan (10), the
Caribbean basin (11), Melanesia (12), and in parts of Africa
(13-15). In some areas where HTLV-I infection is endemic,
prevalence rates as high as 15% have been reported in the general
population. Seroprevalence increases with age; in older age groups,
rates are usually higher among women than men.

In the United States, HTLV-I/II seroprevalence rates among
volunteer blood donors average 0.016% (6). Approximately half of
HTLV-I/II-seropositive blood donors nationwide are infected with
HTLV-I. HTLV-I-infected donors most often report a history of birth
in HTLV-I-endemic countries or sexual contact with persons from the
Caribbean or Japan. Smaller percentages report a history of either
injecting drug use or blood transfusion. Clusters of HTLV-I
infections have also been reported in blacks from the southeastern
United States (16) and in immigrants from HTLV-I-endemic areas
residing in Brooklyn, New York (17).

Transmission

Transmission of HTLV-I occurs from mother to child (18), by
sexual contact (19), by blood transfusion (20), and by sharing
contaminated needles. Mother-to-child transmission occurs primarily
through breast-feeding (21); in HTLV-I-endemic areas, approximately
25% of breast-fed infants born to HTLV-I-seropositive mothers
acquire infection. Recent studies suggest that transmission of
HTLV-I by breast-feeding may be associated with the presence of
maternal antibodies to the HTLV-I transactivating protein, tax
(22), or with elevated maternal titers of total antibodies to
HTLV-I (23). However, the clinical usefulness of these markers has
not been established. Intrauterine or perinatal transmission of
HTLV-I does occur, but it appears to be less frequent than
transmission by breast-feeding; approximately 5% of children born
to infected mothers but not breast-fed acquire infection (24).
Sexual transmission of HTLV-I appears to be more efficient
from males to females than from females to males. In one study of
married couples in Japan, the efficiency of sexual transmission
from males to females was estimated to be 60.8% over a 10-year
period, compared with less than 1% from females to males (25). In
another study, the presence of antibody to tax in the male partner
was associated with sexual transmission to the female partner (26).
In one study in Jamaica, genital ulcer disease in the male was
identified as a risk for female-to-male sexual transmission (27).
In the United States, approximately 25%-30% of sex partners of
HTLV-I/II-seropositive blood donors are also seropositive (28,29).
Transmission of HTLV-I by blood transfusion occurs with
transfusion of cellular blood products (whole blood, red blood
cells, and platelets) but not with the plasma fraction or plasma
derivatives from HTLV-I-infected blood. Seroconversion rates of 44%
to 63% have been reported in recipients of HTLV-I-infected cellular
components in HTLV-I endemic areas (20,30). Lower rates
(approximately 20%) have been reported in recipients of
contaminated cellular components in the United States (31). The
probability of transmission by whole blood or packed red blood
cells appears to diminish with greater duration of product storage;
this finding has been ascribed to depletion of infected cells,
presumably T-lymphocytes (30,32). Sharing blood-contaminated
needles is the likely mode of transmission among injecting drug
users.

HTLV-I is not transmitted by casual contact. Health-care
workers caring for HTLV-I-infected persons need only be concerned
about percutaneous exposure to HTLV-I-contaminated blood. One
health-care worker who unintentionally inoculated himself with
blood from an adult T-cell leukemia/lymphoma patient in Japan is
reported to have seroconverted (33). However, no seroconversions
occurred among 31 other laboratory and health-care workers exposed
to HTLV-I via puncture wounds (34 ). Universal precautions,
recommended for contact with all patients, are adequate to guard
against HTLV-I transmission to health-care workers (35).

ATL is a malignancy of HTLV-I-infected CD4+ T-lymphocytes. The
HTLV-I provirus is monoclonally integrated in the abnormal cell
population. A spectrum of clinical and pathologic features has been
described, including acute, chronic, lymphomatous, and smoldering
forms (36,37). The acute form of ATL is characterized by
infiltration of lymph nodes, viscera, and skin with malignant
cells, resulting in a constellation of clinical features (Table 1).
Circulating abnormal lymphocytes, called flower cells, are
generally seen. Hypercalcemia, abnormal liver function values, and
lytic bone lesions are common. Median survival is 11 months from
diagnosis. Conventional chemotherapy is not curative, and relapses
often occur quickly, although prolonged survival has been reported.
ATL has been estimated to occur in 2%-4% of persons infected with
HTLV-I in regions where HTLV-I is endemic and where early childhood
infection is common (38,39). ATL occurs most frequently among
persons 40-60 years of age, suggesting that a latent period as long
as a few decades may be required for the disease to develop. One
case of ATL in an immunocompromised patient has been reported in
which the infection appears to have been transfusion acquired (40).
HAM/TSP is characterized by progressive, permanent
lower-extremity weakness, spasticity, hyperreflexia, sensory
disturbances, and urinary incontinence (Table 2). In patients with
HAM/TSP, unlike those with multiple sclerosis, the signs and
symptoms do not wax and wane, cranial nerves are not involved, and
cognitive function is not affected. Antibodies to HTLV-I are
characteristically found in the cerebrospinal fluid (41 ).
Treatment with corticosteroids has been reported to be useful in
some cases (42 ). Danazol, a synthetic androgen, reportedly
improves symptoms, including bladder dysfunction (43,44). HAM/TSP
develops in less than 1% of HTLV-I-infected persons (45), is
believed to be immunologically mediated, and affects women more
frequently than men. The latency period for HAM/TSP is shorter than
that for ATL; cases of HAM/TSP have been associated with blood
transfusion, with a median interval of 3.3 years between
transfusion and development of HAM/TSP (46).

Recently, infective dermatitis, a chronic eczema associated
with Staphylococcus aureus and beta-hemolytic streptococcus, has
been reported in Jamaican children infected with HTLV-I (47).
The full spectrum of HTLV-I-associated diseases may include
other disorders. Cases of polymyositis (48), chronic arthropathy
(49), panbronchiolitis (50), and uveitis (51) have been reported in
HTLV-I-infected patients.

HTLV-II

Prevalence

Until recently, partly because of the lack of serologic tests
to differentiate HTLV-II from HTLV-I, no information was available
regarding the seroepidemiology or modes of transmission of HTLV-II.
HTLV-II is prevalent among injecting drug users in the United
States and in Europe (52,53); more than 80% of HTLV-I/II
seropositivity in drug users in the United States is due to HTLV-II
infection (54). HTLV-II also appears to be endemic in American
Indian populations, including the Guaymi Indians in Panama (55 )
and North American Indians in Florida (56) and New Mexico (57).
Approximately half of U.S. volunteer blood donors seropositive for
HTLV-I/II are infected with HTLV-II. HTLV-II-infected blood donors
most often report either a history of injecting drug use or a
history of sexual contact with an injecting drug user (6,58). A
smaller percentage report a history of blood transfusion.

Transmission

HTLV-II is presumed to be transmitted similarly to HTLV-I, but
much less is known about the specific modes and efficiency of
transmission of HTLV-II. One study of 20 non-breast-fed children
born to HTLV-II-infected women in New York City failed to show
evidence of transmission to the newborns (59). The HTLV-II provirus
has been detected in breast milk from HTLV-II-infected mothers
(60), but no data are available regarding transmission to
breast-fed infants.

HTLV-II can be transmitted sexually (61); the most commonly
reported risk factor among HTLV-II-infected female U.S. blood
donors is sexual contact with an injecting drug user (6,58).
HTLV-II can be transmitted by transfusion of cellular blood
products (whole blood, red blood cells, and platelets) (31,32). The
probability of transmission from red blood cells appears to
diminish with greater duration of product storage (31).
The high prevalence of HTLV-II among injecting drug users is
likely due to sharing blood-contaminated needles or other injection
paraphernalia (62).

Diseases

HTLV-II infection has not been clearly associated with any
diseases. The virus was first isolated from two patients with
hairy-cell leukemia (2,63), but no evidence of HTLV-II infection
was found in 21 additional patients with hairy-cell leukemia (64).
In one study, rates of lymphoproliferative illnesses were not found
to be increased in New Mexico, where HTLV-II is present in American
Indians (65). Rare cases of HAM/TSP-like neurologic illnesses (66)
and of mycosis fungoides (67) and large granular lymphocyte
leukemia (68) have been reported in HTLV-II-infected persons. Cases
of erythrodermatitis and bacterial skin infections have been
reported in HIV-1- and HTLV-II-coinfected persons (69).

SEROLOGIC TESTS FOR HTLV-I AND HTLV-II

Serum specimens are screened for antibody to HTLV-I by using
licensed enzyme immunoassays prepared from HTLV-I whole-virus
lysate antigens. These assays vary in their sensitivity to detect
antibodies to HTLV-II (4,5). Initially reactive specimens are
retested in duplicate to minimize the chance that reactivity is due
to technical error. Specimens that are reactive in either of the
duplicate tests are considered repeatably reactive. Specimens that
do not react in either of the duplicate repeat tests are considered
nonreactive (3).

Additional tests, such as the Western immunoblot and the
radioimmunoprecipitation assay, are needed to correctly interpret
repeatably reactive specimens. Such supplementary tests must be
inherently capable of identifying antibodies to the core (gag) and
the envelope (env) proteins of HTLV-I/II. Indirect fluorescent
antibody testing for HTLV-I/II has been used in some laboratories,
but it does not distinguish antibodies to specific HTLV gene
products. None of the supplementary tests have been licensed by the
Food and Drug Administration, but they are available in research
institutions, blood banks, some public health laboratories, and
industrial laboratories, and as in-house tests in some diagnostic
laboratories.

The following criteria for HTLV-I/II seropositivity were
adopted by a U.S. Public Health Service (USPHS) working group in
1988 (3): a specimen that is repeatably reactive by enzyme
immunoassay must demonstrate immunoreactivity to both the gag gene
product p24 and to an env gene product (gp46 and/or gp61/68) to be
considered seropositive for HTLV-I/II. Reactive serum specimens
that do not satisfy these criteria but do show immunoreactivity to
at least one suspected HTLV gene product are designated
"indeterminate." Both Western immunoblot and
radioimmunoprecipitation may be required to determine whether a
specimen is positive or indeterminate. Serum specimens with no
immunoreactivity to any HTLV gene product in additional, more
specific tests are considered false positive. Several studies
involving provirus amplification have supported the accuracy of
these diagnostic criteria; persons whose specimens satisfy the
criteria for positivity are virtually always infected with HTLV-I
or HTLV-II (7,70). In contrast, persons whose specimens are
"indeterminate" are rarely infected with either virus; for those
who are found to be infected, repeat serologic testing frequently
demonstrates seropositivity (70,71). In rare instances, persons
with reactivity to p19 and to an env gene product (gp46 and/or
gp61/68) but without reactivity to p24 have been found to be
infected with HTLV-I/II (72).

An important advance in HTLV serologic testing has been the
development of a recombinant env protein, p21e. Reactivity to p21e
(in either enzyme immunoassay or "spiked" Western immunoblot) has
been found to be highly sensitive for HTLV-I/II infection, being
observed in virtually 100% of infected persons (73). However, the
specificity of the p21e reactivity has been questioned (74,75). For
purposes of notification and counseling, the positivity of samples
showing p21e serologically should be confirmed by tests that detect
env reactivity, such as radioimmunoprecipitation or recombinant
protein-based assays (76), or by polymerase chain reaction until
further information is available concerning this test.
The supplementary serologic tests discussed thus far are
incapable of differentiating antibodies to HTLV-I and HTLV-II. The
relative intensity of the reactivity to the gag proteins p19 and
p24 on the "spiked" Western immunoblot has been used to
differentiate HTLV-I from HTLV-II (77), but such differentiation
may be unreliable (78). Recently, several synthetic peptides and
recombinant proteins have been developed for this purpose (8,9,79).
As with the previously discussed supplementary tests, all these
tests are available for research only. Preliminary data indicate
that such assays can be highly specific in differentiating
antibodies to HTLV-I and HTLV-II (8,9,79). Not all
HTLV-I/II-positive serum specimens, however, can be typed as HTLV-I
or HTLV-II by using these tests. In these cases, more sophisticated
methods, such as provirus amplification or virus isolation, may be
needed to differentiate HTLV-I from HTLV-II infection.

NOTIFICATION AND DEFERRAL OF BLOOD DONORS

In the United States, blood donors whose serum specimens are
repeatably reactive by the HTLV-I enzyme immunoassay and confirmed
as seropositive for HTLV-I/II by the additional specific tests
discussed above are notified and permanently deferred from donating
blood. This deferral policy includes donors confirmed positive with
antibodies to HTLV-I, HTLV-II, or HTLV-I/II (if differentiation
between the infections is not attempted or is unsuccessful). Blood
donors with serum specimens repeatably reactive on screening but
not confirmed as seropositive for HTLV-I/II (a category that
includes false-positive specimens and those indeterminate for HTLV)
should also be notified and deferred if the same result is obtained
on two separate donations. In some blood centers, such donors are
deferred after the first such donation. Persons who are repeatably
reactive on screening but not confirmed as seropositive for
HTLV-I/II should not be told that they are infected with HTLV-I or
HTLV-II. The above policies for donor deferral are based on FDA
recommendations. In addition, FDA recommendations regarding the use
of blood components should be followed.

RECOMMENDATIONS FOR COUNSELING

In consideration of the information presented above, the
following recommendations for counseling HTLV-seropositive persons
have been issued. In instances in which viral typing is possible,
counseling should be virus specific. As noted above, HTLV-I and
HTLV-II are two different retroviruses with differing
epidemiologies and disease associations. The specific
recommendations for persons infected with HTLV-I or HTLV-II should
therefore take these differences into account.

HTLV-I

Persons found to be seropositive for HTLV-I/II according to
the USPHS criteria and positive for HTLV-I by additional testing
should be informed that they are infected with HTLV-I. They should
be told that HTLV-I is not the AIDS virus, that it does not cause
AIDS, and that AIDS is caused by a different virus called HIV. They
should be told that HTLV-I is a lifelong infection. They should be
given information regarding modes and efficiency of transmission,
disease associations, and the probability of developing disease.

In particular, persons infected with HTLV-I should be advised to:

Share the information with their physician

Refrain from donating blood, semen, body organs, or other
tissues

Refrain from sharing needles or syringes with anyone

Refrain from breast-feeding infants

Consider the use of latex condoms to prevent sexual
transmission

If the HTLV-I-positive person is in a mutually monogamous
sexual relationship, testing of the sex partner should be
recommended to help formulate specific counseling advice. If the
sex partner is also positive, no further recommendations are
indicated. If the sex partner is negative, the couple should be
advised that the use of latex condoms can help prevent transmission
of HTLV-I to the negative partner, male or female. Male-infected,
female-non-infected couples desiring pregnancy should be made aware
of the finite risk of sexual transmission of HTLV-I during attempts
at pregnancy and of the small risk for vertical transmission from
mother to infant unrelated to breast-feeding. Such couples might be
advised to use latex condoms at all times except during the fertile
period while they are attempting pregnancy. The use of latex
condoms is strongly recommended for HTLV-I-positive persons with
multiple sex partners or otherwise engaging in non-mutually
monogamous sexual relationships. These persons should be reminded
of the risk of acquiring other sexually transmitted infections,
including HIV.

HTLV-II

Persons found to be seropositive for HTLV-I/II according to
the USPHS criteria and positive for HTLV-II by additional testing
should be informed that they are infected with HTLV-II. They should
be told that HTLV-II is not the AIDS virus, that it does not cause
AIDS, and that AIDS is caused by a different virus called HIV. They
should be told that HTLV-II is a lifelong infection. They should be
given information regarding possible modes of transmission and the
lack of firm disease associations.

In particular, they should be advised to:

Share the information with their physician

Refrain from donating blood, semen, body organs, or other
tissues

Refrain from sharing drug needles or syringes with anyone

Refrain from breast-feeding infants
Although the risks of transmission of HTLV-II by
breast-feeding and of disease from HTLV-II are unknown, the
theoretical risk of transmission and disease, as for HTLV-I, makes
it prudent to recommend that HTLV-II-infected mothers refrain from
breast-feeding when and where safe nutritional alternatives exist.

Consider the use of barrier precautions to prevent sexual
transmission
HTLV-II can be sexually transmitted, but the risks of disease
are unknown. If the HTLV-II-positive person is in a mutually
monogamous sexual relationship, testing of the sex partner should
be recommended to help formulate specific counseling advice. If the
sex partner is also positive, no further recommendations are
indicated. If the sex partner is negative, the couple should be
advised that the use of latex condoms can help prevent transmission
of HTLV-II to the negative partner, male or female. The use of
latex condoms is strongly recommended for HTLV-II-positive persons
with multiple sex partners or otherwise engaging in non-mutually
monogamous sexual relationships. These persons should be reminded
of the risk of acquiring other sexually transmitted infections,
including HIV.

HTLV-I/II

Persons found to be seropositive for HTLV-I/II according to
the USPHS criteria but without differentiation of their infection
should be informed they are positive for HTLV-I/II and that they
are likely infected with either HTLV-I or HTLV-II. Because of the
differences in the epidemiologic and clinical correlates of HTLV-I
and HTLV-II, an effort to type the infection should be made. If
such efforts are unsuccessful, these HTLV-I/II seropositive persons
should be given information regarding possible modes and efficiency
of transmission of HTLV-I and HTLV-II, disease associations of
HTLV-I, and the probability of developing disease. Specific
counseling advice should be the same as for HTLV-I-infected persons
(refer to HTLV-I section).

HTLV Indeterminate

Blood donors with serum specimens that are HTLV-indeterminate
on two occasions at least 3 months apart should be advised that
their specimens were reactive in a screening test for HTLV-I but
that the results could not be confirmed by a second, more specific
test. They should be reassured that "indeterminate" test results
are only rarely caused by HTLV-I or HTLV-II infection. Persons
testing "indeterminate" for HTLV-I/II on one occasion should be
offered retesting to make sure they are not recently infected with
HTLV-I or HTLV-II and in the process of seroconverting. If
subsequent test results are the same, they should be reassured that
they are unlikely to be infected with HTLV-I or HTLV-II.

HTLV False Positive

Blood donors with serum specimens that are repeatably reactive
by HTLV-I enzyme immunoassay but negative by Western immunoblot on
two occasions should be advised that their HTLV-I screening test is
falsely positive and that it could not be confirmed by a second,
more specific test. They should be reassured that they are not
infected with HTLV-I or HTLV-II.

Medical Follow-up

A periodic medical evaluation of HTLV-I- or HTLV-I/II-infected
persons by a physician knowlegeable about these viruses is
recommended. This evaluation might include a physical examination,
including a neurologic examination, and a complete blood count with
peripheral smear examination. Medical evaluation of HTLV-II-infected
persons should be considered optional.

CIO Responsible for this publication: National Center for Infectious Disease,
Division of HIV/AIDS Division of Viral and Rickettsial Diseases

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